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Alpha-1 antitrypsin deficiency

What is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency is an inherited disorder that can cause lung disease in adults and liver disease in adults and children.

The first signs and symptoms of lung disease caused by alpha-1 antitrypsin deficiency usually appear between ages 20 and 50. The earliest symptoms are shortness of breath following mild activity, reduced ability to exercise, and wheezing. Other signs and symptoms can include unintentional weight loss, recurring respiratory infections, fatigue, rapid heartbeat upon standing, and vision abnormalities. Advanced lung disease leads to emphysema, in which small air sacs in the lungs (alveoli) are damaged. Characteristic features of emphysema include difficulty breathing, a hacking cough, and a barrel-shaped chest. Smoking or exposure to tobacco smoke accelerates the appearance of symptoms and damage to the lungs.

About 10 percent of infants and 15 percent of adults with alpha-1 antitrypsin deficiency have liver damage. Signs of liver disease can include a swollen abdomen, swollen feet or legs, and yellowing of the skin and whites of the eyes (jaundice).

In rare cases, alpha-1 antitrypsin deficiency also causes a skin condition known as panniculitis, which is characterized by hardened skin with painful lumps or patches. Panniculitis varies in severity and can occur at any age.

How common is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. For example, in Scandinavia this disorder affects 1 in 1,500 to 3,000 individuals, but it is less common in Asian and black populations. In North America, alpha-1 antitrypsin deficiency affects 1 in 5,000 to 7,000 people.

What genes are related to alpha-1 antitrypsin deficiency?

Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency.

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin. This protein protects the body from being damaged by a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (such as lung tissue) if not carefully controlled by alpha-1 antitrypsin. Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin protein or an abnormal form of the protein that cannot control neutrophil elastase. Uncontrolled, neutrophil elastase destroys alveoli, which can lead to emphysema. The abnormal form of alpha-1 antitrypsin can also accumulate in the liver and may damage this organ.

How do people inherit alpha-1 antitrypsin deficiency?

This condition is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene may be expressed, and both versions contribute to the genetic trait.

The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of the alpha-1 antitrypsin protein. Most people have two copies of the M allele (MM) in each cell. Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin. For example, the S allele produces moderately low levels of this enzyme, and the Z allele produces very little alpha-1 antitrypsin. Individuals with two copies of the Z allele (ZZ) in each cell are likely to have alpha-1 antitrypsin deficiency. Those with the SZ combination have an increased risk of developing lung disorders (such as emphysema), particularly if they smoke.

Worldwide, about 161 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). Individuals with a MS (or SS) combination usually produce enough alpha-1 antitrypsin to protect the lungs. People with MZ alleles, however, have a slightly increased risk of impaired lung or liver function.

Alpha 1-Antitrypsin Deficiency on Wikipedia

'''Alpha 1-antitrypsin deficiency''' ('''A1AD''' or '''Alpha-1''') is a genetic disorder caused by reduced levels of alpha 1-antitrypsin in the blood. It can lead to emphysema and, in some cases, to liver disease.

Signs and symptoms

Symptoms of alpha-1 antitrypsin deficiency include dyspnea, recurring respiratory infections, or obstructive asthma that does not respond to treatment. Individuals with alpha-1 may develop emphysema during their thirties or forties, without a history of significant smoking (although smoking greatly increases the risk for emphysema). A1AD also causes impaired liver function in some patients and may lead to cirrhosis and liver failure (15%). It is the leading cause of liver transplantation in newborns.

Pathophysiology

''Please see alpha 1-antitrypsin for a discussion of the various genotypes and phenotypes associated with A1AD.'' Alpha 1-antitrypsin (AAT) is produced in the liver, and one of its functions is to protect the lungs from the elastase enzyme. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 gram/litre. In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of AAT are reduced to between 40 and 60 percent of normal levels. This is sufficient to protect the lungs from the effects of elastase in people who do not tobacco smoking. However, in individuals with the PiZZ phenotype, AAT levels are less than 15 percent of normal, and patients are likely to develop emphysema at a young age; 50 percent of these patients will develop cirrhosis, because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy biopsy in such cases will reveal Periodic acid-Shiff-positive, diastase-negative granules. Cigarette smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammation ...   [ Read More ]


External Resources

Alpha 1 Awareness Alliance - A site where members of the medical professions and the public can find information about alpha 1-antitrypsin- deficiency. Includes news, reports and links.

MedicineNet - An Alpha-1 antitrypsin deficiency article with details such as what it is, normal lungs and how they work, smoking, risk factors, how it is inherited, signs, symptoms and treatment.

Patient UK - A list of resources and support for persons living in the UK who are interested in Alpha-1 Antitrypsin Deficiency.

Late Manifestation of Alpha-1-antitrypsin Deficiency in the Adult - Literature review of late manifestations including hepatic decompensation and hepatocellular cancer in alpha-1-antitrypsin deficiency.

Understanding Alpha-1 Antitrypsin Deficiency - Information on signs and symptoms of this disorder, as well as risk factors and treatment.

Alpha1 Antitrypsine Deficiency - One man's perspective and journey with A1AD and a list of links and other resources from the internet.

Alpha 1 Association - Organization which attempts to identify those affected by alpha-1-antitrypsin deficiency and to improve their quality of their lives through support, education, advocacy and research.

Alpha One Registry - Database of individuals with Alpha1-Antitrypsin Deficiency, a genetic disorder associated with pulmonary emphysema and liver disease. Includes participant benefits, a bulletin board, and recent findings.


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